Trichloroethylene (TCE) is a major industrial chemical that has become a common environmental pollutant. Human studies have shown that children and pregnant women are vulnerable to low level TCE exposure. Thus, there is an urgent need to understand the health effects associated with developmental TCE exposure. In our published studies, continuous exposure to TCE throughout gestation and early life in MRL+/+ mice induced CD4+ T cell proinflammatory cytokines in juvenile mice at postnatal day (PND) 42. These systemic immune effects were associated adverse neurologic and behavioral effects including altered cerebellar redox status and increased aggressive behavior commensurate with alterations in the expression of neuroinflammatory and neurodevelopmental genes. The potential clinical significance of these findings is underscored by the fact that these alterations have been identified in several neurologic disorders including autism and Parkinson's Disease. Systemic immune degregulation accompanies several of these disorders and may provide a mechanistic link between environmental toxicants, loss of neuroimmune homeostasis, and adverse neurologic outcome. Our primary goal is to fill current knowledge gaps that will enable us to further define the specific susceptibility window(s) required for immunologic, neurologic, and associated behavioral alterations linked with developmental TCE exposure. This proposal will test the hypothesis that developmental exposure to TCE induces a systemic proinflammatory response that dysregulates peripheral immune and neuroimmune programming to promote adverse neurobehavioral outcome. MRL+/+ mice will be exposed to 0, 0.01 and 0.1 mg/ml TCE during three distinct developmental windows including 1) prenatal exposure [gestational day (GD) 0-GD18], 2) postnatal exposure (PND0-PND42), and 3) continuous exposure (GD0-PND42). Male offspring will be sacrificed at PND42 to define the specific developmental window (s) affected by TCE exposure in the following Aims. Aim 1 will investigate the peripheral immune response in control and TCE-exposed PND42 male offspring and in dams at mid gestation (GD7) and mid lactation (PND10). Aim 2 will investigate the neuroimmune response in PND42 male offspring exposed to TCE by determining the impact of TCE on biomarkers of neuroinflammation and oxidative stress in defined brain regions. Neuropathology assessment will delineate whether TCE-induced neuroinflammatory changes stem from peripheral immune cell infiltration or originate within the brain. Aim 3 will provide a comprehensive neurobehavioral evaluation in PND 42 male offspring from each treatment group. Using this model to better understand how a common environmental toxicant modulates the neural and immune developmental program could contribute significantly to the development of effective screening, therapeutic, and preventative strategies for many environmentally-related neurologic disorders. PUBLIC HEALTH RELEVANCE: Immune disturbances mediated by environmental influences at critical developmental windows may have far reaching consequences for childhood health and may enhance susceptibility to neurodevelopmental disorders. This proposal will define the developmental window responsible for trichloroethylene-induced immunologic, neurologic, and neurobehavioral dysfunction.